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Funding Information: We acknowledge funding from the Finnish Cultural Foundation, Academy of Finland (Decisions Nos. 294625, 306845, and 327326), Instrumentarium Science Foundation, and European Research Council (ERC Synergy) under the European Union’s Horizon 2020 research and innovation programme (ConnectToBrain; Grant Agreement No. 810377). M.N. and P.N. were supported by the Basic Research Program of HSE University, P.N. was supported by Aalto AScI Visiting Researcher Programme, and M.N was supported by the NIH Brain Initiative Biology and Biophysics of Neural Stimulation and Recording Technologies (1R01NS112183-01A1). In addition, we would like to thank Science-IT at Aalto University School of Science for computational resources. | openaire: EC/H2020/810377/EU//ConnectToBrain Objective. Transcranial magnetic stimulation (TMS) induces an electric field (E-field) in the cortex. To facilitate stimulation targeting, image-guided neuronavigation systems have been introduced. Such systems track the placement of the coil with respect to the head and visualize the estimated cortical stimulation location on an anatomical brain image in real time. The accuracy and precision of the neuronavigation is affected by multiple factors. Our aim was to analyze how different factors in TMS neuronavigation affect the accuracy and precision of the coil-head coregistration and the estimated E-field. Approach. By performing simulations, we estimated navigation errors due to distortions in magnetic resonance images (MRIs), head-to-MRI registration (landmark- and surface-based registrations), localization and movement of the head tracker, and localization of the coil tracker. We analyzed the effect of these errors on coil and head coregistration and on the induced E-field as determined with simplistic and realistic head models. Main results. Average total coregistration accuracies were in the range of 2.2-3.6 mm and 1°; precision values were about half of the accuracy values. The coregistration errors were mainly due to head-to-MRI registration with average accuracies 1.5-1.9 mm/0.2-0.4° and precisions 0.5-0.8 mm/0.1-0.2° better with surface-based registration. The other major source of error was the movement of the head tracker with average accuracy of 1.5 mm and precision of 1.1 mm. When assessed within an E-field method, the average accuracies of the peak E-field location, orientation, and magnitude ranged between 1.5 and 5.0 mm, 0.9 and 4.8°, and 4.4 and 8.5% across the E-field models studied. The largest errors were obtained with the landmark-based registration. When computing another accuracy measure with the most realistic E-field model as a reference, the accuracies tended to improve from about 10 mm/15°/25% to about 2 mm/2°/5% when increasing realism of the E-field model. Significance. The results of this comprehensive analysis help TMS operators to recognize the main sources of error in TMS navigation and that the coregistration errors and their effect in the E-field estimation depend on the methods applied. To ensure reliable TMS navigation, we recommend surface-based head-to-MRI registration and realistic models for E-field computations.

openaire: EC/H2020/810377/EU//ConnectToBrain Background: Prefrontal theta oscillations are involved in neuronal information transfer and retention. Phases along the theta cycle represent varied excitability states, whereby high-excitability states correspond to high-frequency neuronal activity and heightened capacity for plasticity induction, as demonstrated in animal studies. Human studies corroborate this model and suggest a core role of prefrontal theta activity in working memory (WM). Objective/Hypothesis: We aimed at modulating prefrontal neuronal excitability and WM performance in healthy humans, using real-time EEG analysis for triggering repetitive transcranial magnetic stimulation (rTMS) theta-phase synchronized to the left dorsomedial prefrontal cortex. Methods: 16 subjects underwent 3 different rTMS interventions on separate days, with pulses triggered according to the individual's real-time EEG activity: 400 rTMS gamma-frequency (100 Hz) triplet bursts applied during either the negative peak of the prefrontal theta oscillation, the positive peak, or at random phase. Changes in cortical excitability were assessed with EEG responses following single-pulse TMS, and behavioral effects by using a WM task. Results: Negative-peak rTMS increased single-pulse TMS-induced prefrontal theta power and theta-gamma phase-amplitude coupling, and decreased WM response time. In contrast, positive-peak rTMS decreased prefrontal theta power, while no changes were observed after random-phase rTMS. Conclusion: Findings point to the feasibility of EEG-TMS technology in a theta–gamma phase–amplitude coupling mode for effectively modifying WM networks in human prefrontal cortex, with potential for therapeutic applications.

BackgroundTranscranial magnetic stimulation (TMS) allows non-invasive stimulation of the cortex. In multi-locus TMS (mTMS), the stimulating electric field (E-field) is controlled electronically without coil movement by adjusting currents in the coils of a transducer.ObjectiveTo develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region.MethodsWe designed and manufactured a planar 5-coil mTMS transducer to allow controlling the maximum of the induced E-field within a cortical region approximately 30 mm in diameter. We developed electronics with a design consisting of independently controlled H-bridge circuits to drive up to six TMS coils. To control the hardware, we programmed software that runs on a field-programmable gate array and a computer. To induce the desired E-field in the cortex, we developed an optimization method to calculate the currents needed in the coils. We characterized the mTMS system and conducted a proof-of-concept motor-mapping experiment on a healthy volunteer. In the motor mapping, we kept the transducer placement fixed while electronically shifting the E-field maximum on the precentral gyrus and measuring electromyography from the contralateral hand.ResultsThe transducer consists of an oval coil, two figure-of-eight coils, and two four-leaf-clover coils stacked on top of each other. The technical characterization indicated that the mTMS system performs as designed. The measured motor evoked potential amplitudes varied consistently as a function of the location of the E-field maximum.ConclusionThe developed mTMS system enables electronically targeted brain stimulation within a cortical region.

Background Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of the cortex. In multi-locus TMS (mTMS), the stimulating electric field (E-field) is controlled electronically without coil movement by adjusting currents in the coils of a transducer. Objective To develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region. Methods We designed and manufactured a planar 5-coil mTMS transducer to allow controlling the maximum of the induced E-field within a cortical region approximately 30 mm in diameter. We developed electronics with a design consisting of independently controlled H-bridge circuits to drive up to six TMS coils. To control the hardware, we programmed software that runs on a field-programmable gate array and a computer. To induce the desired E-field in the cortex, we developed an optimization method to calculate the currents needed in the coils. We characterized the mTMS system and conducted a proof-of-concept motor-mapping experiment on a healthy volunteer. In the motor mapping, we kept the transducer placement fixed while electronically shifting the E-field maximum on the precentral gyrus and measuring electromyography from the contralateral hand. Results The transducer consists of an oval coil, two figure-of-eight coils, and two four-leaf-clover coils stacked on top of each other. The technical characterization indicated that the mTMS system performs as designed. The measured motor evoked potential amplitudes varied consistently as a function of the location of the E-field maximum. Conclusion The developed mTMS system enables electronically targeted brain stimulation within a cortical region., Highlights • Multi-locus TMS system with six independent H-bridge channels. • 5-coil transducer to control the electric field within a 30-mm-diameter cortical region. • Algorithm for targeting the electric field. • Automatic motor mapping without physical coil movement.

BackgroundTranscranial magnetic stimulation (TMS) is widely used in brain research and treatment of various brain dysfunctions. However, the optimal way to target stimulation and administer TMS therapies, for example, where and in which electric field direction the stimuli should be given, is yet to be determined.ObjectiveTo develop an automated closed-loop system for adjusting TMS parameters (in this work, the stimulus orientation) online based on TMS-evoked brain activity measured with electroencephalography (EEG).MethodsWe developed an automated closed-loop TMS–EEG set-up. In this set-up, the stimulus parameters are electronically adjusted with multi-locus TMS. As a proof of concept, we developed an algorithm that automatically optimizes the stimulation orientation based on single-trial EEG responses. We applied the algorithm to determine the electric field orientation that maximizes the amplitude of the TMS– EEG responses. The validation of the algorithm was performed with six healthy volunteers, repeating the search twenty times for each subject.ResultsThe validation demonstrated that the closed-loop control worked as desired despite the large variation in the single-trial EEG responses. We were often able to get close to the orientation that maximizes the EEG amplitude with only a few tens of pulses.ConclusionOptimizing stimulation with EEG feedback in a closed-loop manner is feasible and enables effective coupling to brain activity.

Transcranial magnetic stimulation (TMS) is widely used in brain research and treatment of various brain dysfunctions. However, the optimal way to target stimulation and administer TMS therapies, for example, where and in which electric field direction the stimuli should be given, is yet to be determined.To develop an automated closed-loop system for adjusting TMS parameters (in this work, the stimulus orientation) online based on TMS-evoked brain activity measured with electroencephalography (EEG).We developed an automated closed-loop TMS-EEG set-up. In this set-up, the stimulus parameters are electronically adjusted with multi-locus TMS. As a proof of concept, we developed an algorithm that automatically optimizes the stimulation orientation based on single-trial EEG responses. We applied the algorithm to determine the electric field orientation that maximizes the amplitude of the TMS-EEG responses. The validation of the algorithm was performed with six healthy volunteers, repeating the search twenty times for each subject.The validation demonstrated that the closed-loop control worked as desired despite the large variation in the single-trial EEG responses. We were often able to get close to the orientation that maximizes the EEG amplitude with only a few tens of pulses.Optimizing stimulation with EEG feedback in a closed-loop manner is feasible and enables effective coupling to brain activity.

Sensorimotor µ-rhythm phase is correlated with corticospinal excitability. Transcranial magnetic stimulation (TMS) of motor cortex results in larger motor evoked potentials (MEPs) during the negative peak of the EEG oscillation as extracted with a surface Laplacian. However, the anatomical source of the relevant oscillation is not clear and demonstration of the relationship is sensitive to the choice of EEG montage.Here, we compared two EEG montages preferentially sensitive to oscillations originating from the crown of precentral gyrus (dorsal premotor cortex) vs. postcentral gyrus (secondary somatosensory cortex). We hypothesized that the EEG signal from precentral gyrus would correlate more strongly with MEP amplitude, given that the corticospinal neurons are located in the anterior wall of the sulcus and the corticospinal tract has input from premotor cortex.Real-time EEG-triggered TMS of motor cortex was applied in 6 different conditions in randomly interleaved order, 3 phase conditions (positive peak, negative peak, random phase of the ongoing µ-oscillation), and each phase condition for 2 different EEG montages corresponding to oscillations preferentially originating in precentral gyrus (premotor cortex) vs. postcentral gyrus (somatosensory cortex), extracted using FCC3h vs. C3 centered EEG montages.The negative vs. positive peak of sensorimotor µ-rhythm as extracted from the C3 montage (postcentral gyrus, somatosensory cortex) correlated with states of high vs. low corticospinal excitability (p 0.001), replicating previous findings. However, no significant correlation was found for sensorimotor µ-rhythm as extracted from the neighboring FCC3 montage (precentral gyrus, premotor cortex). This implies that EEG-signals from the somatosensory cortex are better predictors of corticospinal excitability than EEG-signals from the motor areas.The extraction of a brain oscillation whose phase corresponds to corticospinal excitability is highly sensitive to the selected EEG montage and the location of the EEG sensors on the scalp. Here, the cortical source of EEG oscillations predicting response amplitude does not correspond to the cortical target of the stimulation, indicating that even in this simple case, a specific neuronal pathway from somatosensory cortex to primary motor cortex is involved.

Electroencephalography (EEG) concurrently collected with functional magnetic resonance imaging (fMRI) is heavily distorted by the repetitive gradient coil switching during the fMRI acquisition. The performance of the typical template-based gradient artifact suppression method can be suboptimal because the artifact changes over time. Gradient artifact residuals also impede the subsequent suppression of ballistocardiography artifacts. Here we propose recording continuous EEG with temporally sparse fast fMRI (fast fMRI-EEG) to minimize the EEG artifacts caused by MRI gradient coil switching without significantly compromising the field-of-view and spatiotemporal resolution of fMRI. Using simultaneous multi-slice inverse imaging to achieve whole-brain fMRI with isotropic 5-mm resolution in 0.1 ​s, and performing these acquisitions once every 2 ​s, we have 95% of the duty cycle available to record EEG with substantially less gradient artifact. We found that the standard deviation of EEG signals over the entire acquisition period in fast fMRI-EEG was reduced to 54% of that in conventional concurrent echo-planar imaging (EPI) and EEG recordings (EPI-EEG) across participants. When measuring 15-Hz steady-state visual evoked potentials (SSVEPs), the baseline-normalized oscillatory neural response in fast fMRI-EEG was 2.5-fold of that in EPI-EEG. The functional MRI responses associated with the SSVEP delineated by EPI and fast fMRI were similar in the spatial distribution, the elicited waveform, and detection power. Sparsely interleaved fast fMRI-EEG provides high-quality EEG without substantially compromising the quality of fMRI in evoked response measurements, and has the potential utility for applications where the onset of the target stimulus cannot be precisely determined, such as epilepsy.

Background: Transcranial magnetic stimulation (TMS) allows focal, non-invasive stimulation of the cortex. A TMS pulse is inherently weakly coupled to the cortex; thus, magnetic stimulation requires both high current and high voltage to reach sufficient intensity. These requirements limit, for example, the maximum repetition rate and the maximum number of consecutive pulses with the same coil due to the rise of its temperature. Objective: To develop methods to optimise, design, and manufacture energy-efficient TMS coils in realistic head geometry with an arbitrary overall coil shape. Methods: We derive a semi-analytical integration scheme for computing the magnetic field energy of an arbitrary surface current distribution, compute the electric field induced by this distribution with a boundary element method, and optimise a TMS coil for focal stimulation. Additionally, we introduce a method for manufacturing such a coil by using Litz wire and a coil former machined from polyvinyl chloride. Results: We designed, manufactured, and validated an optimised TMS coil and applied it to brain stimulation. Our simulations indicate that this coil requires less than half the power of a commercial figure-of-eight coil, with a 41% reduction due to the optimised winding geometry and a partial contribution due to our thinner coil former and reduced conductor height. With the optimised coil, the resting motor threshold of abductor pollicis brevis was reached with the capacitor voltage below 600 V and peak current below 3000 A. Conclusion: The described method allows designing practical TMS coils that have considerably higher efficiency than conventional figure-of-eight coils. (C) 2017 Elsevier Inc. All rights reserved.

Beamformers are applied for estimating spatiotemporal characteristics of neuronal sources underlying measured MEG/EEG signals. Several MEG analysis toolboxes include an implementation of a linearly constrained minimum-variance (LCMV) beamformer. However, differences in implementations and in their results complicate the selection and application of beamformers and may hinder their wider adoption in research and clinical use. Additionally, combinations of different MEG sensor types (such as magnetometers and planar gradiometers) and application of preprocessing methods for interference suppression, such as signal space separation (SSS), can affect the results in different ways for different implementations. So far, a systematic evaluation of the different implementations has not been performed. Here, we compared the localization performance of the LCMV beamformer pipelines in four widely used open-source toolboxes (MNE-Python, FieldTrip, DAiSS (SPM12), and Brainstorm) using datasets both with and without SSS interference suppression. We analyzed MEG data that were i) simulated, ii) recorded from a static and moving phantom, and iii) recorded from a healthy volunteer receiving auditory, visual, and somatosensory stimulation. We also investigated the effects of SSS and the combination of the magnetometer and gradiometer signals. We quantified how localization error and point-spread volume vary with the signal-to-noise ratio (SNR) in all four toolboxes. When applied carefully to MEG data with a typical SNR (3–15 ​dB), all four toolboxes localized the sources reliably; however, they differed in their sensitivity to preprocessing parameters. As expected, localizations were highly unreliable at very low SNR, but we found high localization error also at very high SNRs for the first three toolboxes while Brainstorm showed greater robustness but with lower spatial resolution. We also found that the SNR improvement offered by SSS led to more accurate localization., Highlights • Different beamformer implementations are reported to sometimes yield differing source estimates for the same MEG data. • We compared beamformers in four major open-source MEG analysis toolboxes. • All toolboxes provide consistent and accurate results with 3–15-dB input SNR. • However, localization errors are high at very high input SNR for the tested scalar beamformers. • We discuss the critical differences between the implementations.

Transcranial magnetic stimulation (TMS) is often targeted using a model of TMS-induced electric field (E). In such navigated TMS, the E-field models have been based on spherical approximation of the head. Such models omit the effects of cerebrospinal fluid (CSF) and gyral folding, leading to potentially large errors in the computed E-field. So far, realistic models have been too slow for interactive TMS navigation. We present computational methods that enable real-time solving of the E-field in a realistic five-compartment (5-C) head model that contains isotropic white matter, gray matter, CSF, skull and scalp. Using reciprocity and Geselowitz integral equation, we separate the computations to coil-dependent and -independent parts. For the Geselowitz integrals, we present a fast numerical quadrature. Further, we present a moment-matching approach for optimizing dipole-based coil models. We verified and benchmarked the new methods using simulations with over 100 coil locations. The new quadrature introduced a relative error (RE) of 0.3–0.6%. For a coil model with 42 dipoles, the total RE of the quadrature and coil model was 0.44–0.72%. Taking also other model errors into account, the contribution of the new approximations to the RE was 0.1%. For comparison, the RE due to omitting the separation of white and gray matter was >11%, and the RE due to omitting also the CSF was >23%. After the coil-independent part of the model has been built, E-fields can be computed very quickly: Using a standard PC and basic GPU, our solver computed the full E-field in a 5-C model in 9000 points on the cortex in 27 coil positions per second (cps). When the separation of white and gray matter was omitted, the speed was 43–65 cps. Solving only one component of the E-field tripled the speed. The presented methods enable real-time solving of the TMS-induced E-field in a realistic head model that contains the CSF and gyral folding. The new methodology allows more accurate targeting and precise adjustment of stimulation intensity during experimental or clinical TMS mapping.

The question “What is the spatial resolution of EEG/MEG?” can only be answered with many ifs and buts, as the answer depends on a large number of parameters. Here, we describe a framework for resolution analysis of EEG/MEG source estimation, focusing on linear methods. The spatial resolution of linear methods can be evaluated using the resolution matrix, which contains the point-spread and cross-talk functions (PSFs and CTFs), respectively. Both of them have to be taken into account for a full characterization of spatial resolution. They can be used to compute a range of quantitative resolution metrics, which should cover at the last three aspects of those functions: localization accuracy, spatial extent, and relative amplitude. Here, we first provide a tutorial-style introduction to resolution analysis of linear source estimation methods. We then apply these concepts to evaluate the benefit of combining EEG and MEG measurements, and to compare weighted and normalized L2-minimum-norm estimation and spatial filters. We confirm and extend previous results, showing that adding EEG to MEG improves spatial resolution, and that different methods offer different compromises among different resolution criteria. We hope that our approach will help EEG/MEG researchers in the interpretation of source estimation results, the design of new experiments, and the development of new MEG systems.

openaire: EC/H2020/686865/EU//BREAKBEN Co-registration between structural head images and functional MEG data is needed for anatomically-informed MEG data analysis. Despite the efforts to minimize the co-registration error, conventional landmark- and surface-based strategies for co-registering head and MEG device coordinates achieve an accuracy of typically 5–10 mm. Recent advances in instrumentation and technical solutions, such as the development of hybrid ultra-low-field (ULF)MRI–MEG devices or the use of 3D-printed individualized foam head-casts, promise unprecedented co-registration accuracy, i.e., 2 mm or better. In the present study, we assess through simulations the impact of such an improved co-registration on MEG connectivity analysis. We generated synthetic MEG recordings for pairs of connected cortical sources with variable locations. We then assessed the capability to reconstruct source-level connectivity from these recordings for 0–15-mm co-registration error, three levels of head modeling detail (one-, three- and four-compartment models), two source estimation techniques (linearly constrained minimum-variance beamforming and minimum-norm estimation MNE)and five separate connectivity metrics (imaginary coherency, phase-locking value, amplitude-envelope correlation, phase-slope index and frequency-domain Granger causality). We found that beamforming can better take advantage of an accurate co-registration than MNE. Specifically, when the co-registration error was smaller than 3 mm, the relative error in connectivity estimates was down to one-third of that observed with typical co-registration errors. MNE provided stable results for a wide range of co-registration errors, while the performance of beamforming rapidly degraded as the co-registration error increased. Furthermore, we found that even moderate co-registration errors (>6 mm, on average)essentially decrease the difference of four- and three- or one-compartment models. Hence, a precise co-registration is important if one wants to take full advantage of highly accurate head models for connectivity analysis. We conclude that an improved co-registration will be beneficial for reliable connectivity analysis and effective use of highly accurate head models in future MEG connectivity studies.

Simultaneous electroencephalography (EEG) and magnetoencephalography (MEG) recordings of neuronal activity from epileptic patients reveal situations in which either EEG or MEG or both modalities show visible interictal spikes. While different signal-to-noise ratios (SNRs) of the spikes in EEG and MEG have been reported, a quantitative relation of spike source orientation and depth as well as the background brain activity to the SNR has not been established. We investigated this quantitative relationship for both dipole and patch sources in an anatomically realistic cortex model. Altogether, 5600 dipole and 3300 patch sources were distributed on the segmented cortical surfaces of two volunteers. The sources were classified according to their quantified depths and orientations, ranging from 20 mm to 60 mm below the skin surface and radial and tangential, respectively. The source time-courses mimicked an interictal spike, and the simulated background activity emulated resting activity. Simulations were conducted with individual three-compartment boundary element models. The SNR was evaluated for 128 EEG, 102 MEG magnetometer, and 204 MEG gradiometer channels. For superficial dipole and superficial patch sources, EEG showed higher SNRs for dominantly radial orientations, and MEG showed higher values for dominantly tangential orientations. Gradiometers provided higher SNR than magnetometers for superficial sources, particularly for those with dominantly tangential orientations. The orientation dependent difference in SNR in EEG and MEG gradually changed as the sources were located deeper, where the interictal spikes generated higher SNRs in EEG compared to those in MEG for all source orientations. With deep sources, the SNRs in gradiometers and magnetometers were of the same order. To better detect spikes, both EEG and MEG should be used.

We introduce a source localization method of the MUltiple Signal Classification (MUSIC) family that can locate brain-signal sources robustly and reliably, irrespective of their temporal correlations. The method, double-scanning (DS) MUSIC, is based on projecting out the topographies of source candidates during topographical scanning in a way that breaks the mutual dependence of highly correlated sources, but keeps the uncorrelated sources intact. We also provide a recursive version of DS-MUSIC (RDS-MUSIC), which overcomes the peak detection problem present in the non-recursive methods. We compare DS-MUSIC and RDS-MUSIC with other localization techniques in numerous simulations with varying source configurations, correlations, and signal-to-noise ratios. DS- and RDS-MUSIC were the most robust localization methods; they had a high success rate and localization accuracy for both uncorrelated and highly correlated sources. In addition, we validated RDS-MUSIC by showing that it successfully locates bilateral synchronous activity from measured auditory-evoked MEG.